Li Ying, Wang Shanshan, Zhang Ruidan, Gong Yingying, Che Yulu, Li Kening, Pan Zongfu
Department of Pharmaceutical Sciences, Institute of Pharmacology, Zhejiang University of Technology, Hangzhou, China.
Department of Pharmacy, Center for Clinical Pharmacy, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
Front Cardiovasc Med. 2025 Feb 13;12:1510082. doi: 10.3389/fcvm.2025.1510082. eCollection 2025.
Cardiovascular disease (CVD) caused by atherosclerosis (AS) remains the leading cause of mortality in developed countries. Understanding cellular heterogeneity within the inflammatory microenvironment is crucial for advancing disease management strategies. This study investigates the regulatory functions of distinct cell populations in AS pathogenesis, focusing on the interaction between vascular smooth muscle cell (VSMC)-derived ITLN1 foam cells and SPP1 FABP5 macrophages.
We employed single-cell RNA sequencing to characterize cell populations within AS plaques. Correlation analyses and the CellChat package were utilized to elucidate intercellular communication networks among various cell types. The functional roles of key subsets of macrophages and VSMCs were assessed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Pseudotime trajectory analysis was conducted to explore the dynamics of VSMC differentiation. Additionally, spatial transcriptomics analysis was used to demonstrate the physical interactions between different cell subpopulations.
We identified significant infiltration of macrophage clusters in AS, with SPP1 FABP5 macrophages being highly enriched in AS plaques. These macrophages were associated with lipid transport, storage, and cell migration pathways. A distinct subset of ITLN1 foam cells derived from VSMCs exhibited robust expression of foam cell markers and lipid metabolism-related genes. Pseudotime trajectory analysis indicated that ITLN1 foam cells represent a terminal stage of VSMC differentiation, characterized by elevated expression of genes linked to lipid synthesis and AS progression. Spatial transcriptomics and CellChat analysis revealed a significant interaction between ITLN1 foam cells and SPP1 FABP5 macrophages, mediated by the MIF-(CD74 + CD44) and SPP1-CD44 ligand-receptor axes.
Our findings underscore the critical crosstalk between ITLN1 foam cells and SPP1 macrophages in promoting lipid accumulation and AS progression. Targeting this cell-cell interaction may offer new therapeutic avenues for managing atherosclerosis. Further validation of these mechanisms is necessary to develop effective immunotherapeutic strategies against AS.
动脉粥样硬化（AS）所致的心血管疾病（CVD）仍是发达国家的主要死因。了解炎症微环境中的细胞异质性对于推进疾病管理策略至关重要。本研究调查了不同细胞群体在AS发病机制中的调节功能，重点关注血管平滑肌细胞（VSMC）来源的ITLN1泡沫细胞与SPP1 FABP5巨噬细胞之间的相互作用。
我们采用单细胞RNA测序来表征AS斑块内的细胞群体。利用相关性分析和CellChat软件包来阐明不同细胞类型之间的细胞间通信网络。使用基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路分析来评估巨噬细胞和VSMC关键亚群的功能作用。进行伪时间轨迹分析以探索VSMC分化的动态过程。此外，利用空间转录组学分析来证明不同细胞亚群之间的物理相互作用。
我们在AS中发现巨噬细胞簇显著浸润，SPP1 FABP5巨噬细胞在AS斑块中高度富集。这些巨噬细胞与脂质运输、储存和细胞迁移途径相关。源自VSMC的ITLN1泡沫细胞的一个独特亚群表现出泡沫细胞标志物和脂质代谢相关基因的强烈表达。伪时间轨迹分析表明，ITLN1泡沫细胞代表VSMC分化的终末阶段，其特征是与脂质合成和AS进展相关的基因表达升高。空间转录组学和CellChat分析揭示了ITLN1泡沫细胞与SPP1 FABP5巨噬细胞之间存在显著相互作用，由MIF-（CD74 + CD44）和SPP1-CD44配体-受体轴介导。
我们的研究结果强调了ITLN1泡沫细胞与SPP1巨噬细胞之间在促进脂质积累和AS进展方面的关键相互作用。靶向这种细胞间相互作用可能为治疗动脉粥样硬化提供新的治疗途径。为了开发针对AS的有效免疫治疗策略，有必要对这些机制进行进一步验证。
